tbuckley/cabot-search huggingface dataset:
Tumor transcriptomic profile in patients (pts) with advanced prostate cancer (PCa) with cribriform and signet ring-like histologies.
Authors: Tori Seasor, Michael Balatico, Beverly Chigarira, Kamal Kant Kant Sahu, Jong Taek Kim, Anna P Matynia, Marc Barry, Daniel Joseph Albertson, Jon Mahlow, Umang Swami, Neeraj Agarwal, Deepika Sirohi
Journal: Journal of Clinical Oncology (2023)

259 Background: Histological subtypes of Pca are generally associated with worse clinical outcomes. Here in, we hypothesize that histological subtypes of PCa, e.g., cribriform, and signet ring-like, may have distinct genomic characteristics that may unravel new therapeutic targets. Methods: In this IRB-approved study, patient-level data were collected retrospectively. Eligibility: Pathology slides of advanced PCa (with cribriform and signet ring-like histology, and non-cribriform/signet ring-like histology as control) with transcriptomic data available. Only Gleason grade 4 or 5 were included to ensure homogeneity in population. Histology was independently reviewed by two genitourinary pathologists. RNA-sequencing of treatment naive primary prostate tissue was performed by a CLIA certified lab. DeSeq2 analysis was implemented in Bioconductor Software to analyze differentially expressed genes in patients with cribriform versus non-cribriform and signet ring-like versus non-signet ring-like histology. DeSeq2 results included the Log2 Fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were then subjected to Gene Set Enrichment Analysis (GSEA) in order to identify pathways upregulated or downregulated in each cohort. All bioinformatic analysis was conducted in R-Studio, version 4.1.1. Statistical significance level was predetermined at 0.05. Results: 34 patients were included: cribriform histology n=17, signet ring-like n=4, control non-cribriform/signet ring-like PCa n=13 (control were matched for age, PSA and disease volume). Compared to control, upregulated pathways in cribriform histology included adipogenesis, fatty acid and xenobiotic metabolism, while the down regulated pathways included mitotic spindle, G2M checkpoint and E2F targets. In signet ring-like histology, inflammatory response pathways were upregulated; DNA repair, MYC targets and androgen response pathways were downregulated. Conclusions: Cribriform, and signet ring-like histologic subtypes were noted to have distinct genomic expression profile. These data may need further validation and will guide further drug development.
Neoadjuvant cisplatin-based chemotherapy followed by selective bladder preservation chemoradiotherapy (CRT) in muscle-invasive urothelial carcinoma of bladder (MIBC): A combined retrospective analysis of two prospective studies.
Authors: Joohyun Hong, Daeho Choi, Hyun Hwan Sung, Byong Chang Jeong, Se Hoon Park
Journal: Journal of Clinical Oncology (2023)

496 Background: Bladder preservation CRT in patients with a clinical complete response (cCR) following neoadjuvant cisplatin-based chemotherapy is one of the promising treatment strategies for MIBC. A combined analysis of raw data from two prospective phase II studies was performed to better evaluate the feasibility of selective bladder preservation CRT. Methods: The analysis was based on primary efficacy data from two independent studies, including 76 MIBC patients receiving neoadjuvant chemotherapy followed by bladder preservation CRT. The efficacy data included metastasis-free survival (MFS) and disease-free survival (DFS). For the present analysis, starting point of survivals was defined as the date of commencing CRT. Results: Sixty-four patients received gemcitabine/cisplatin (GC) combination chemotherapy in neoadjuvant setting, and 12 received nivolumab plus GC. After completion of planned neoadjuvant chemotherapy, 66 patients with a cCR and 10 who did not have a cCR but refused surgery were treated with CRT. With a median follow-up of 45 (95% CI, 41-48) months, a total of 39 recurrences was observed (51%): metastatic (n=28) and within the urinary tract (n=11). Median DFS or MFS was not reached. The 12- and 24-month DFS rates were 81% and 66%, respectively. MFS rates at 12- and 24-month were 87% and 75%, respectively. Both DFS (P=0.055) and MFS (P=0.014; HR 0.38; 95% CI, 0.17-0.85) appeared to be affected by the achievement of a cCR. Conclusions: The strategy of neoadjuvant chemotherapy followed by selective bladder preservation CRT based on the cCR is feasible in the treatment of MIBC.
Germline testing for men with prostate cancer: Need to broaden the indications in Europe?
Authors: Elena Trevisi, Kira-Lee Koster, Karl Heinimann, Ursina Zuerrer, Fabio Turco, Davide Giovanni Bosetti, Ilaria Colombo, Silvia Maitz, Marta Nerone, Aurelius Gabriel Omlin, Ursula Vogl, Silke Gillessen, Rossella Graffeo
Journal: Journal of Clinical Oncology (2023)

383 Background: The clinical role of germline testing (GT) for prostate cancer (PC) is rapidly increasing due to the growing implications of precision medicine in metastatic disease, where genetic results can address eligibility for novel targeted treatments. Thus, ESMO and NCCN guidelines recommend GT for all metastatic PC individuals, whereas American testing criteria are more broad and include family history and other tumor features, such as high-risk disease, or intraductal or cribriform histology. Methods: We have retrospectively collected and analyzed clinical and genetic features of men with PC who underwent single-gene or multi-gene GT at some Swiss Institutions with expertise in hereditary cancers from July 2018 until October 2022. All patients (pts) have given written informed consent for research. Results: 109 men with PC underwent GT and received pre- and post-test counseling. Of these, 54 (50%) were metastatic, 34 (31%) had high-risk localized disease according to NCCN criteria, 7 (6%) presented cribriform or intraductal histology. A significant family history, as defined by current NCCN guidelines, was found in 79 (72%). 67 (61%) had no pathogenic (P) or likely pathogenic (LP) variants; 25 (23%) had a variant of unknown significance (VUS); 17 (16%) were found to have a P/LP variant in the following genes: BRCA2 (8), ATM (4), BRIP1 (1), FANCA (1), NBN (1), POT1 (1), TP53 (1). Among these 17 pts, the median age at diagnosis was 66 (45-80), 10 had metastatic disease, 5 had high-risk localized disease, 14 had a family history and 5 had a personal history of another cancer. Only 6 pts were &lt;60 years old at the time of diagnosis. Cascade screening was offered to 16 families (94%). Conclusions: Our preliminary data support the increasing role of GT in PC and suggest the need to expand its indications. In this cohort, 7/17 (41%) of men with localized PC were found to carry P/LP variants and would not have met the criteria to undergo GT according to current European guidelines. GT may have treatment implications for metastatic PC pts whereas in early stage disease can inform cancer risk and screening for pts and their male and female relatives.
Pathogenic <i>BRAF</i> mutations in prostate cancer: Frequency and distribution.
Authors: Elisa M. Ledet, Elizabeth Mauer, Calvin Y. Chao, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2023)

257 Background: Human cancers are known to harbor mutations in BRAF, a rare but clinically significant finding. BRAF p. V600E is the most common hot spot mutation and has been well described, however other activating mutations are less well studied. Herein we evaluate the landscape of BRAF pathogenic/likely pathogenic (P/LP) variations in prostate cancer patients. Methods: De-identified records from patients with primary prostate cancer who underwent NGS with Tempus xF (ctDNA, 105 genes) or xT (tissue, DNAseq of 648 genes, 500× coverage, full transcriptome RNAseq for a subset of patients) were analyzed from a real-world dataset. Results: There were 5,902 patients identified with prostate cancer who underwent any Tempus xT testing, of whom 85 (1.4%) harbored a P/LP BRAF mutation. Of these 85 patients, the most prevalent BRAF mutation identified was BRAF K601E (Lys601Glu) (36% of total), followed by Gly469Ala (18%) and Leu597Arg (8%, Table) There were 4,177 patients identified with primary prostate cancer who underwent any Tempus xF testing, of whom 50 (1.2%) harbored a P/LP BRAF mutation. Similarly, the most prevalent BRAF mutation identified was BRAF K601E (26%). Conclusions: This study presents the first large-scale genomic characterization of BRAF mutations in patients with prostate cancer using both tissue and ctDNA NGS analysis. Among thousands of samples from prostate cancer patients, K601E was the most common BRAF mutation. This confirms findings of smaller studies and has implications for developmental therapeutics. Further studies should document the natural history of BRAF K601E in prostate cancer. [Table: see text]
Carboplatin in metastatic castrate resistant prostate cancer: A retrospective study of heavily pretreated patients (COMPACT).
Authors: Lara Pemberton, Connor Allen, Eleanor Handel, Andrew James Weickhardt, Ben Tran, Megan Crumbaker, Jeremy David Shapiro, Gail P. Risbridger, David William Pook
Journal: Journal of Clinical Oncology (2023)

158 Background: Despite a lack of up-to-date clinical trial data, many clinicians advocate the use of Carboplatin monotherapy to treat patients with advanced Castrate Resistant Prostate Cancer (CRPC) who have exhausted multiple other treatment options. The aim of this study was to determine the overall survival (OS) and response rate in patients with advanced CRPC treated with Carboplatin monotherapy after progressing on other chemotherapy agents. Methods: Retrospective multicentre study of the use of Carboplatin in advanced CRPC patients in Australia. Demographic data, PSA response rates, survival data and Carboplatin treatment protocols, such as dose and duration, were collected. Exploratory analyses on potential prognostic parameters were performed. Results: 51 patients received Carboplatin: median age 68 (range 55–86 years). Most patients (78.3%) received Carboplatin AUC 5 at 3-weekly intervals. The median number of cycles of Carboplatin was 3 (range 1-17). Median time on treatment was 63 days (range 1-441). Median overall survival was 29.4 weeks (IQR 11.7 weeks). 6 (11.8%) patients had a PSA response ≥50%. The median time to PSA progression on Carboplatin was 67 days (range 15-418). 16 patients (31%) required a dose delay or reduction and 8 patients (15.6%) ceased Carboplatin secondary to side effects/ toxicity. Conclusions: Our findings demonstrate that in heavily pre-treated CRPC, Carboplatin has a modest benefit in a minority of patients with a low rate of toxicity in the advanced prostate cancer population.
Efficacy of subsequent treatments in patients who progressed to mCRPC following treatment with apalutamide for nonmetastatic castration-resistant prostate cancer (nmCRPC): A post-hoc analysis of the SPARTAN phase III trial.
Authors: Stephane Oudard, Boris A. Hadaschik, Laurent Antoni, Joris Diels, Irene Luccarini, Pushpike Thilakarathne, Matthew Raymond Smith, Eric Jay Small
Journal: Journal of Clinical Oncology (2023)

157 Background: Apalutamide (Apa) delays the onset of metastases and extends survival in nmCRPC. However, the benefit of subsequent therapy for metastatic castration resistant prostate cancer (mCRPC) following progression on Apa remains inadequately explored. Methods: A post-hoc analysis of SPARTAN, a randomized phase III (NCT01946204), double-blind, placebo-controlled trial with Apa for the treatment of men with nmCRPC was undertaken in order to assess the impact of post-protocol treatment. Patients included in this analysis were SPARTAN patients who developed mCRPC while on Apa and received a first subsequent therapy for mCRPC (the “Next Cohort”). The index date of the analysis was the initiation of first subsequent treatment for mCRPC. The baseline characteristics of the Next Cohort (reported from the time of initial randomization because updated characteristics at the index date could not be derived) were compared to those of the ITT Apa arm in SPARTAN. Subsequent overall survival (sOS) and subsequent progression-free survival per physician assessment (sPFS) were calculated from the index date using Kaplan-Meier method. Results: At study completion, 237 patients remained on Apa without progression, while 311 were included in the Next Cohort. Of these, 241 (77.5%) received abiraterone acetate plus prednisone (AAP) provided by the sponsor as an option as first subsequent treatment, 29 (9.3%) received docetaxel; 20 (6.4%) enzalutamide and 21 other treatments (6.8%). Compared to the ITT Apa arm in SPARTAN, a higher proportion of the Next Cohort had PSA doubling time ≤6 months (79.1% vs 71.5%) and a PSA value above median at baseline, and experienced poorer PSA response (51% PSA90 overall response rate vs 62%) whilst on apalutamide treatment. The median sPFS and sOS were 6.8 months (95% confidence interval, CI, 5.8-7.9) and 20.0 months (95% CI, 17.0-22.6), respectively. Choice of subsequent next treatment did not appear to have an impact on sPFS and sOS. Conclusions: Limitations of this analysis include its retrospective nature and the lack of randomization to first line mCRPC therapy and related potential confounding, and the inclusion of patients who had progressed at SPARTAN study completion with associated poorer prognosis. Nevertheless, the analysis suggests comparable efficacy of selected first line mCRPC therapies, following progression on Apa for nmCRPC. Clinical trial information: NCT01946204 . [Table: see text]
The effect of reduced dose of apalutamide on skin adverse events in advanced prostate cancer: A multicenter retrospective study.
Authors: Shingo Hatakeyama, Ryuji Tabata, Naoki Fujita, Toshikazu Tanaka, Takahiro Yoneyama, Satoshi Sato, Chikara Ohyama
Journal: Journal of Clinical Oncology (2023)

151 Background: We aimed to evaluate the effect of a reduced dose of apalutamide on skin-related adverse events (AEs) and castration-sensitive prostate cancer (CRPC)-free survival in patients with advanced prostate cancer. Methods: We retrospectively evaluated 35 patients with non-metastatic CRPC and 72 treatment naïve metastatic castration-sensitive prostate cancer (mCSPC) who were treated with apalutamide. The primary outcome was the effect of apalutamide dose-reduction on skin AEs. The secondary outcomes included the effect of apalutamide dose-reduction on skin AE in patents with small body size, post-skin AEs discontinuation rate, and the effect of apalutamide dose-reduction on CRPC-free survival in patients with mCSPC treated with upfront apalutamide plus androgen deprivation therapy. Results: Of 107 patients, 65 (60.7%) and 42 (39.3%) patients were treated with full- and reduced-dose of apalutamide, respectively. The skin AEs rate was not significantly different between the groups (55% vs. 43%, P = 0.761). The incident of skin AEs in the reduced dose of apalutamide were significantly lower in patients with small body size (body weight &lt;67kg and body mass index &lt; 24kg/m 2 ) than those in other body sizes. Apalutamide discontinuation rate after skin AEs was significantly different between the full-dose (50%) and reduced-dose (16.7%) groups. Of 72 patients with mCSPC, the CRPC-free survival was not significantly different between the full- and reduced-dose groups. Conclusions: A reduced dose of apalutamide was not significantly associated with the incident of skin AEs. However, dose reduction for patients with small body size may decrease skin AEs without sacrificing oncological outcome.
Impact of run-in treatment with abiraterone acetate and prednisone (AAP) in the MAGNITUDE study of niraparib (NIRA) and AAP in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.
Authors: Elena Castro, Kim N. Chi, Shahneen Sandhu, David Olmos, Gerhardt Attard, Marniza Saad, Andrea Juliana Gomes, Dana E. Rathkopf, Matthew Raymond Smith, Taek Won Kang, Felipe Melo Cruz, Umberto Basso, Gary Mason, Adam del Corral, Shiva Dibaj, Daphne Wu, Brooke Diorio, Angela Mennicke Lopez- Gitlitz, Deniz Tural, Eric Jay Small
Journal: Journal of Clinical Oncology (2023)

172 Background: NIRA/AAP significantly improved outcomes in pts with mCRPC and HRR gene alterations, particularly in BRCA, in the phase 3 MAGNITUDE study. As a practical measure, pts were permitted to receive up to 4 mos of AAP (in 1L mCRPC) prior to randomization to allow time for genomic testing. We evaluated the impact of AAP run-in treatment on the efficacy of NIRA/AAP. Methods: 423 pts with mCRPC and HRR gene alterations were randomized 1:1 to receive NIRA/AAP or placebo (PBO)/AAP. At the prespecified second interim analysis, a sensitivity analysis based on the duration of AAP run-in was conducted. Pts with BRCA alterations were also analyzed separately. Results: Median duration of prior AAP treatment received was 1.9 (range, 0.3–4.1) mos. Pts receiving AAP ≤2 mos had similar benefit (radiographic progression-free survival [rPFS] hazard ratio [HR], 0.69 [95% confidence interval [CI], 0.36-1.30]; time to cytotoxic chemotherapy [TCC] HR, 0.52 [95% CI, 0.24-1.11]; time to symptomatic progression [TSP] HR, 0.32 [95% CI, 0.13-0.79]; Table) to pts not receiving any prior AAP. rPFS benefit was not demonstrated in pts who had previously received AAP &gt;2 – 4 mos: HR, 1.47 (95% CI, 0.66-3.30). Findings were consistent in the BRCA population. Conclusions: Pts receiving a short run-in (≤2 mos) of AAP alone obtained similar benefit from NIRA/AAP as those who received both NIRA/AAP together for initial treatment of mCRPC. While interpretation of data is limited by the small sample size and event numbers, for pts where NIRA/AAP is being considered as therapy, AAP may be initiated during HRR testing and combination treatment should be initiated expeditiously once HRR positivity is established to attain maximal treatment benefit. Clinical trial information: NCT03748641 . [Table: see text]
Current and Emerging Pharmacological Targets and Treatments of Urinary Incontinence and Related Disorders
Authors: Martin C. Michel, Linda Cardozo, Christopher J. Chermansky, Francisco Cruz, Yasuhiko Igawa, Kyu-Sung Lee, Arun Sahai, Alan J. Wein, Karl-Erik Andersson
Journal: Pharmacological Reviews (2023)

Overactive bladder syndrome with and without urinary incontinence and related conditions, signs, and disorders such as detrusor overactivity, neurogenic lower urinary tract dysfunction, underactive bladder, stress urinary incontinence, and nocturia are common in the general population and have a major impact on the quality of life of the affected patients and their partners. Based on the deliberations of the subcommittee on pharmacological treatments of the 7th International Consultation on Incontinence, we present a comprehensive review of established drug targets in the treatment of overactive bladder syndrome and the aforementioned related conditions and the approved drugs used in its treatment. Investigational drug targets and compounds are also reviewed. We conclude that, despite a range of available medical treatment options, a considerable medical need continues to exist. This is largely because the existing treatments are symptomatic and have limited efficacy and/or tolerability, which leads to poor long-term adherence. <h3>Significance Statement</h3> Urinary incontinence and related disorders are prevalent in the general population. While many treatments have been approved, few patients stay on long-term treatment despite none of them being curative. This paper provides a comprehensive discussion of existing and emerging treatment options for various types of incontinence and related disorders.
G Protein-Coupled Receptor Pharmacology—Insights from Mass Spectrometry
Authors: Hsin-Yung Yen, Ali Jazayeri, Carol V. Robinson
Journal: Pharmacological Reviews (2023)

G protein-coupled receptors (GPCRs) are key drug targets due to their involvement in many physiological processes. The complexity of receptor pharmacology however is influenced by multiple interactions with various types of ligands and protein transducers representing significant challenges for drug discovery. The ability of mass spectrometry to observe both the binding of ligand molecules such as lipids, ions or drugs and their impact on interaction with transducers provides an exciting opportunity to probe many aspects that are difficult to track directly in cell-based systems. From the early days, when hydrogen deuterium exchange (HDX) experiments were used to probe the different conformations of GPCRs, through to the most recent insights in which the intact receptor-G protein/arrestin complexes associated with small molecules can be preserved by mass spectrometry, this review highlights the potential of mass spectrometry techniques for in-depth investigations of GPCR biology. Herein, we will describe the utility of mass spectrometry (MS) including HDX-MS, cross-linking and native-MS, in investigating GPCR pharmacology. Specifically, we will include ligand/drug interactions and G<sub>i/s </sub>protein-coupling and illustrate and how these techniques can lead to the discovery of endogenous allosteric ligands and thereby offer a new perspective for drug discovery of GPCRs. <b>Significance Statement</b> GPCRs represent the largest family of druggable protein targets that interact with a diverse array of ligands, from metal ions and small molecules through to peptides and proteins. These extracellular stimuli are translated allosterically into intracellular signals mediated by transducer proteins. Typically, activation of GPCRs relies on binding of endogenous or exogenous agonists to stabilize the receptors in active conformations. Recent developments in MS enable capture of the extent of GPCR activation and discovery of allosteric modulators of downstream signaling.
Potassium Channels in Parkinson’s Disease: Potential Roles in Its Pathogenesis and Innovative Molecular Targets for Treatment
Authors: Xiaoyi Chen, Yunjiang Feng, Ronald J. Quinn, Dean L. Pountney, Des R. Richardson, George D. Mellick, Linlin Ma
Journal: Pharmacological Reviews (2023)

Parkinson9s disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the midbrain. The loss of neurons results in a subsequent reduction of dopamine in the striatum, which underlies the core motor symptoms of PD. To date, there are no effective treatments to stop, slow, or reverse the pathological progression of dopaminergic neurodegeneration. This unfortunate predicament is because of the current early stages in understanding the biological targets and pathways involved in PD pathogenesis. Ion channels have become emerging targets for new therapeutic development for PD due to their essential roles in neuronal function and neuroinflammation. Potassium channels are the most prominent ion channel family and have been shown to be critically important in PD pathology because of their roles in modulating neuronal excitability, neurotransmitter release, synaptic transmission, and neuroinflammation. In this review, members of the subfamilies of voltage-gated K<sup>+</sup> channels, inward rectifying K<sup>+</sup> channels, and Ca<sup>2+</sup>-activated potassium channels are described. Evidence of the role of these channels in PD aetiology is discussed together with the latest views on related pathological mechanisms and their potential as biological targets for developing neuroprotective drugs for PD. <b>Significance Statement</b> Parkinson9s disease (PD) is the second most common neurodegenerative disorder, featuring progressive degeneration of dopaminergic neurons in the midbrain. It is a multifactorial disease involving multiple risk factors and complex pathobiological mechanisms. Mounting evidence suggests that ion channels play vital roles in the pathogenesis and progression of PD by regulating neuronal excitability and immune cell function. Therefore, they have become "hot" biological targets for PD, as demonstrated by multiple clinical trials of drug candidates targeting ion channels for PD therapy.